A Liver-X-Receptor Ligand, T0901317, Attenuates IgE Production and Airway Remodeling in Chronic Asthma Model of Mice

Abstract

The liver-X-receptors have shown anti-inflammatory ability in several animal models of respiratory disease. Our purpose is to investigate the effect of LXR ligand in allergen-induced airway remodeling in mice. Ovalbumin-sensitized mice were chronically challenged with aerosolized ovalbumin for 8 weeks. Some mice were administered a LXR agonist, T0901317 (12.5, 25, 50 mg/kg bodyweight) before challenge. Then mice were evaluated for airway inflammation, airway hyperresponsiveness and airway remodeling. T0901317 failed to attenuate the inflammatory cells and Th2 cytokines in bronchoalveolar lavage fluid. But the application of T0901317 reduced the thickness of airway smooth muscle and the collagen deposition. Meanwhile, T0901317 treatment evidently abolished the high level of OVA-specific IgE, TGF-β1 and MMP-9 in lung. So LXRs may attenuate the progressing of airway remodeling, providing a potential treatment of asthma.

liver X receptors inhibit pulmonary inflammation and airway remodeling induced by ozone exposure in mice

“…Although growing evidence has supported that the activation of LXRs contribute to the inhibition of in ammation in vivo and in vitro [19][20][21][22], the LXRs failed to affect allergic inflammation [22]. So it is important to identify the roles of LXRs in different airway diseases.…”

“…Asthma and COPD are characterized by chronic airway in ammation. In a previous study, the investigators have proven that in an asthma mice model, the application of T0901317 cannot reduce the in ammatory cells and Th2 cytokines in the BALF [22]. This makes it more valuable and meaningful to determine how T0901317 decreases the number of in ammatory cells and cytokines in an ozone-induced airway in ammation model.…”

The liver X receptor agonist AZ876 protects against pathological cardiac hypertrophy and fibrosis without lipogenic side effects

“…TGFβ is critically involved in the pathogenesis of both hypertrophic and fibrotic remodelling by stimulating hypertrophic growth of cardiomyocytes, proliferation of cardiac fibroblasts, including their transition to myofibroblasts, as well as the deposition of ECM proteins . A cross‐talk between LXRs and TGFβ signalling via Smad2/3 interaction has been proposed, and T09 activation of LXRs has been shown to decrease Tgfβ1 in other diseased organs susceptible to fibrotic remodelling, including diabetic nephropathy and chronic asthma‐induced airway remodelling …”

“…16 A cross-talk between LXRs and TGF signalling via Smad2/3 interaction has been proposed, 17 and T09 activation of LXRs has been shown to decrease Tgf 1 in other diseased organs susceptible to fibrotic remodelling, including diabetic nephropathy 18 and chronic asthma-induced airway remodelling. 19 Since AZ876 agonism imparted dual effects on myocardial hypertrophy and fibrosis, mechanistically it is plausible that paracrine signalling from cardiomyocytes responding to hypertrophic stimuli influences fibroblast activation. 20 In support of this notion, we found marked attenuation of fibrosis in transgenic mice with cardiomyocyte-specific LXR overexpression subjected to TAC and Ang II stimulation (Cannon et al, unpublished data and Fstl3, which are known to be secreted by myocytes and cause paracrine activation of adjacent fibroblasts.…”

Regulation of Adaptive Immunity in Health and Disease by Cholesterol Metabolism

“…An apoE mimetic peptide was also recently shown to suppress AHR/remodeling, Th2 and Th17 cytokines, and eosinophilia in the HDM model through an LDLR-dependent mechanism [85]. Also on the therapeutic frontier, studies suggest a potential therapeutic role for synthetic LXR agonists in asthma models [88], consistent with their reported anti-inflammatory efficacy in contact dermatitis models [89]. In the section on statins below, we discuss emerging roles for statins in asthma at further length.…”